Field of the Invention
The present invention relates to pharmaceutical compositions for a combination therapy with a corticosteroid and exosomes. By means of the combination therapy diseases such as osteoarthritis, arthritis and/or degenerative spinal diseases can be treated, wherein the treatment is preferably carried out locally.
Technical Background
Osteoarthritis in Germany refers to “joint wear” to a higher degree than typical for a certain age. It is accompanied by a loss of cartilage in the respective joint, which results in pain and function deterioration. Excess strain, congenital or traumatic causes such as joint malpositions or also bone deformation through bone diseases like osteoporosis are viewed as causes. It can also result from another disease such as joint inflammation or accompany effusion caused by excess strain.
Generally all joints can be affected by osteoarthritic changes. In Germany the disease is most frequently located in the knee joint. Osteoarthritis is one of the most common reasons for seeking advice at a general practitioner's practice. Approximately 10% of the population in Western countries suffer from osteoarthritis. If osteoarthritis diseases of the small vertebral joints and the degenerative intervertebral disc diseases are added, even approx. 15%-20% of the population are affected. The risk of suffering from osteoarthritis increases with age. About two thirds of people over 65 years are affected by the disease, however, not all persons affected also suffer from the symptoms.
For the treatment of osteoarthritis some therapy forms are already known. This includes conservative (e.g. medicinal) therapies as well as surgical procedures to the point of replacing the complete joint by a prosthesis. In order to avoid these extensive and irreversible interventions, an effective medicinal treatment is generally preferred to delay the point in time of a complete joint replacement as far as possible.
However, many medicinal treatments also have disadvantages. On the one hand this is due to the side effects of the medicaments themselves, but their effects are also partially limited.
A medicinal agent frequently used for treating osteoarthritis and rheumatoid arthritis is cortisone (also applied locally) and related corticosteroids. These are administered systemically in the case of RA and locally as an injection into the affected joint in the case of osteoarthritis. However, it is found that the positive effect of a corticosteroid administration in osteoarthritis as well as rheumatoid arthritis already significantly decreases after just one week. This is clinically proven by randomized studies and clinical experience. In RA it is tried by continuous administration of cortisone to systemically keep a high level of the agent, however this is problematic due to an increase of side effects and reduction of the therapeutical effect in continuous administration.
Exosomes are small vesicles coated by a lipid membrane, which are found in the extracellular space for example of the human body. They are formed and secreted by cells by separation from the cellular plasma membrane. Normally these exosomes also contain proteins which they have adopted from their original cell. Methods for the preparation and administration of exosomes are described for example in patent application WO 2006/007529 A2. In in vitro induction of prophylactically or therapeutically effective proteins such as e.g. IL-1Ra by incubation of a blood sample in an appropriate vessel such as e.g. a syringe, exosomes are formed. Consequently, Orthokine for example contains exosomes. The formation of exosomes may be increased by means of adding an additive which stimulates the formation of exosomes. The concentration of exosomes may be increased by centrifugation with high centrifugal forces, for example. The use of exosomes in the treatment of rheumatoid arthritis is known per se.
A further medicament which can be used for treating osteoarthritis is the protein IL-1Ra, which is produced naturally in the body, or an isoform or fragment thereof, which shows a similar activity. Interleukin-1-receptor antagonist (IL-1Ra) binds to the same receptors on the cell surface as interleukin-1 (IL-1), but does not trigger the signaling cascade normally caused by IL-1Ra binding. By binding to the IL-1 receptor, IL-1Ra blocks the binding of IL-1 and thus prevents its transduction of signals and thus the inflammatory effect of IL-1 on the target cells.
Treatment of patients with autologous serum in which IL-1Ra was enriched, is known in the state of the art. IL-1Ra used in this way is also called Orthokine. A recombinant IL-1Ra fragment, Anakinra, in contrast did not show any effects in the treatment of osteoarthritis compared to a placebo treatment. Anakinra is an isoform of the human interleukin-1 receptor antagonist shortened to amino acids 26-177 and terminally L-methionylated and has a sequence length of 153 amino acids. The preparation is done for example by means of Escherichia coli strains using recombinant methods.
In the light of the state of the art, the problem to be solved was thus to provide a medicinal treatment of osteoarthritis, which is more effective and particularly shows a good long-term efficacy. The treatment should furthermore preferably have a good efficacy, preferably long-term efficacy, in arthritis, particularly rheumatoid arthritis.